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WO2009070766A2 - Fonctionnalisation de micro et nanoparticules en vue de les fixer de manière sélective sur des surfaces biominérales de calcium - Google Patents

Fonctionnalisation de micro et nanoparticules en vue de les fixer de manière sélective sur des surfaces biominérales de calcium Download PDF

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Publication number
WO2009070766A2
WO2009070766A2 PCT/US2008/085038 US2008085038W WO2009070766A2 WO 2009070766 A2 WO2009070766 A2 WO 2009070766A2 US 2008085038 W US2008085038 W US 2008085038W WO 2009070766 A2 WO2009070766 A2 WO 2009070766A2
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Prior art keywords
particle
magnetic
ferrous
biological
derivatives
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WO2009070766A3 (fr
Inventor
Stacey L. Mcleroy
Bruce E. Gnade
Jeffrey A. Cadeddu
Margaret Pearle
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University of Texas System
University of Texas at Austin
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University of Texas System
University of Texas at Austin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/22—Implements for squeezing-off ulcers or the like on inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; for invasive removal or destruction of calculus using mechanical vibrations; for removing obstructions in blood vessels, not otherwise provided for
    • A61B17/221—Gripping devices in the form of loops or baskets for gripping calculi or similar types of obstructions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
    • A61B34/70—Manipulators specially adapted for use in surgery
    • A61B34/73—Manipulators for magnetic surgery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B2017/00831—Material properties
    • A61B2017/00876—Material properties magnetic

Definitions

  • the present invention relates in general to the field of biomaterials, and more particularly, to compositions, methods, tools and kits for the functionalization of biomaterials and their selective capture under physiologic conditions.
  • Kidney stone disease is a major health problem affecting 5-10% of the U.S. population and accounts for over $2 billion in annual expenses.
  • Compositions and methods are taught herein to assist in the retrieval of biomaterials, e.g., kidney stone fragments, which have been modified to increase magnetic susceptibility.
  • biomaterials e.g., kidney stone fragments
  • invasive surgical procedures associated with significant surgical morbidity and time lost from work.
  • the introduction of extracorporeal techniques for stone fragmentation and refinements in endoscopic surgery has decreased greatly the morbidity associated with stone surgery without compromising success.
  • the kidneys are the organs of urinary filtration and excretion where the urine accumulates into and drains from the renal-collecting system.
  • the urinary filtrate enters the collecting system via the renal papillae where the small collecting tubules coalesce.
  • the urine then travels through a branching system of calyces which coalesce to form a single renal pelvis that then drains into the ureter. As most stones over 5 mm diameter cannot pass through this collecting system, surgical fragmentation and/or extraction is necessary.
  • the present invention includes compositions and method of magnetizing a biological particle by contacting a biological particle with a ferrous or magnetic particle that is able to specifically bind the biological particle; and reacting the biological particle with the ferrous or magnetic particle under physiological conditions, wherein the ferrous or magnetic particle causes the biological particle to become attractable magnetically.
  • the biological particle is a kidney stone or fragment thereof.
  • the ferrous or magnetic particle further includes an agent that specifically binds the surface of the biological target with high affinity such as antibodies, aptamers, peptides, polypetides, proteins, amino acids, polyamino acids, small organic molecules, phosphonic acids, carboxylic acids, long chain phosphonic and long chain carboxylic acids.
  • the biological particle may include at least one of Apatite, Calcium Oxalate Monohydrate, Calcium Oxalate Dihydrate, Brushite Uric Acid, Cysteine and Struvite.
  • the ferrous particle is, e.g., Fe, Fe 2 ⁇ 3, Fe3 ⁇ 4 or FeC.
  • the biological particle comprises a kidney stone or fragment thereof.
  • the ferrous or magnetic particle is suspended in a physiological solution, e.g., saline.
  • the biological particles and the ferrous or magnetic particles are located in a anatomical lumen and further comprising the step of removing the biological particle with a device that attracts the ferrous or magnetic particle.
  • the ferrous or magnetic particle may have a size of, e.g., between 5 nm to 1 mm. In certain aspects, the ferrous or magnetic particle may have a size of 5, 10, 50, 100, 200, 250, 350, 400, 500, 600, 750, 800, 900, nanometers or even 1, 5, 10, 25, 50, 200, 250, 350, 400, 500, 600, 750, 800, 900 micrometers or even 1 mm.
  • the ferrous or magnetic particle further comprises an agent that specifically binds the surface of the biological target selected from proteins that interact with calcium-based biominerals, such as carboxylic acid- rich proteins, osteopontin, Tamm-Horsfall protein, and prothrombin fragment 1; small carboxyl-containing molecules such as citrate are known to have an inhibitory effect on the growth of Calcium Oxalate crystals in healthy urine; and calcium-binding protein motifs that includes the EF-hand, which have carboxylic -rich residues (GIu, Asp) and Glycine for flexibility; and short peptides that are rich in polar or charged residues.
  • an agent that specifically binds the surface of the biological target selected from proteins that interact with calcium-based biominerals, such as carboxylic acid- rich proteins, osteopontin, Tamm-Horsfall protein, and prothrombin fragment 1; small carboxyl-containing molecules such as citrate are known to have an inhibitory effect on the growth of Calcium Oxalate crystals in healthy urine; and calcium-
  • the present invention includes a medical device having, e.g., an expansible member having a proximal end, a delivery state, and a deployed state; wherein the deployed state comprises an at least partially magnetic portion for deployment within an anatomical lumen for the capture of a magnetic target material, and wherein the deployed state is configured to retrieve the material from within the anatomical lumen.
  • the device may also have an elongated flexible tube including a distal end and a proximal end, the tube defining a channel extending from the proximal end of the tube to an aperture at the distal end and wherein the deployed portion of the member is housed within the channel prior to deployment within the anatomical lumen.
  • the delivery state is a compressed state.
  • the device extends proximally out of the channel and is configured to control axial movement of the expansible member relative to the tube.
  • the portion of the medical device that attracts the coated kidney stone can be an attachment to medical devices that are presently used to view and/or collect kidney stones.
  • the attachment can be part of a kit that includes the kidney stone-binding particles and may optionally include irrigation solutions, written materials that describe the methods for use of the materials and the attachment of the functionalized kidney-tone attracting device.
  • the deployed state is further defined as expansible, wherein the expansible state that has a proximal end and a distal end, and markers are positioned proximate at least one of the distal and proximal ends of the expansible member.
  • the expansible member has a tapered proximal end to facilitate releasable engagement with a distal end of the instrument.
  • the expansible member includes a protrusion at the proximal end to facilitate engagement between the instrument and the expansible member.
  • the expansible member may include a material that exhibits an expansion/compression size ratio of approximately 10: 1. Examples of expansible member may be made from a biocompatible polymer, plastic, nylon, polyester, or metal.
  • the expansible member comprises a cavity.
  • the expansible member may also define one or more holes formed therein for passing irrigation therethrough in the deployed state.
  • the device further includes grasping forceps, a collapsible basket, a hook, a net, a lasso, or a sponge.
  • the expansible member expands to fill a cross-sectional area of an anatomical lumen in the expanded, deployed state.
  • the present invention also includes compositions and methods for immobilizing a magnetic biological material in a body by inserting a magnetic expansible member into an anatomical lumen of the body, the expansible member having a delivery state, an expanded state, and a proximal end detachably engaged with a distal end of an instrument; positioning the instrument to deploy the expansible member such that the expansible member transforms from the delivery state to the expanded state at a treatment site within the anatomical lumen; and capturing biological particles within the lumen that have been modified in situ to be attracted magnetically.
  • the method also includes inserting an expansible member includes providing an elongated flexible tube including a distal end and a proximal end, the tube defining a channel extending from the proximal end of the tube to an aperture at the distal end, and wherein the expansible member is housed within the channel prior to deployment at a treatment site.
  • the step of positioning the instrument is used to deploy the expansible member and includes moving the instrument relative to the tube to control axial movement of the expansible member beyond the channel.
  • the expansible member includes a material that expands to the expanded state when unrestrained.
  • the expansible member is deployed distally beyond the material to be immobilized such that the expansible member at least partially occludes the anatomical lumen.
  • the method further includes the step of performing a lithotripsy procedure on the biomaterial.
  • the method may also include the step of irrigating the anatomical lumen with a composition comprising a ferrous or magnetic particle that is able to specifically bind the biological material.
  • the method also includes the step of retrieving the immobilized biological material by proximally pulling the expansible member through the anatomical lumen.
  • the anatomical lumen includes an interior surface and the expansible member expands to contact the interior surface of the anatomical lumen.
  • the expansible member has a proximal end and a distal end, and markers are positioned proximate the distal and proximal ends of the expansible member.
  • the step of positioning further includes visualizing the position of the markers through a medical imaging device.
  • the step of retrieving the immobilized material also includes engaging fragmented immobilized material with the device.
  • the present invention includes devices and methods for stabilizing a target biomaterial in a patient's body by contacting a first material comprising a magnetic portion with a target biomaterial to cause the biomaterial to become magnetic in a body lumen under physiologic conditions; inserting a medical device comprising a magnetically attracting end, wherein the magnetized biomaterial is attracted to the medical device; and removing the biomaterial from the patient's body.
  • the target biomaterial is broken into at least two fragments by technique selected from the group consisting of extra-corporeal shock wave lithotripsy, intra-corporeal shock wave lithotripsy, or Holmium laser fragmentation.
  • the present invention includes a kit that includes one or more containers comprising a ferrous or magnetic particle that is able to specifically bind to a biological particle, and one or more devices comprising an end that is magnetic and able to attract the ferrous or magnetic particle in a body lumen.
  • the present invention includes a method of magnetizing and moving a biological particle that includes contacting a biological particle with a ferrous particle that is able to specifically bind the biological particle; reacting, adsorbing, or adhering the biological particle with the ferrous particle under physiological conditions, wherein the ferrous or magnetic particle causes the biological particle to become attractable magnetically; and directing a magnet, e.g., an external or internal magnet or magnetic field, to the location of the ferrous particle to move the particle using the magnetic field generated by the magnet.
  • the biological particle is a kidney stone or fragment thereof.
  • the ferrous particle includes an agent that specifically binds the surface of the biological target with high affinity such as antibodies, aptamers, peptides, polypeptides, proteins, protein fragments, amino acids, polyamino acids, phosphonic acids, carboxylic acids, long chain phosphonic and long chain carboxylic acids.
  • the biological particle may be, for example, at least one of Apatite, Calcium Oxalate Dihydrate, Calcium Oxalate Monohydrate, Struvite, Cysteine, Brushite and Uric Acid.
  • the ferrous particle includes Fe 2 ⁇ 3 or Fe3 ⁇ 4 .
  • the biological particles and the ferrous or magnetic particles are located in a anatomical lumen and further comprising the step of removing the biological particle with a device that attracts the ferrous or magnetic particle.
  • the present invention includes a method of identifying a biological particle comprising: contacting a biological particle with a ferrous particle that is able to specifically bind the biological particle and a fluorescent dye; reacting, adsorbing, or adhering the biological particle with the ferrous particle under physiological conditions, wherein the ferrous or magnetic particle causes the biological particle to become attractable magnetically and fluorescent; directing a magnet to the location of the ferrous particle to move the particle using the magnetic field generated by the magnet; and pointing a light that excites the fluorescent dye to provide visualization of the particles.
  • Another embodiment of the present invention includes a method of identifying a biological particle by contacting a biological particle with a ferrous particle that is able to specifically bind the biological particle and a dye; reacting, adsorbing, or adhering the biological particle with the ferrous particle under physiological conditions, wherein the ferrous or magnetic particle causes the biological particle to become attractable magnetically; directing a magnet to the location of the ferrous particle to move the particle using the magnetic field generated by the magnet; and pointing a light that excites the dye to provide visualization of the particles.
  • the dye comprises a fluorescent dye and/or a visible dye.
  • the dye comprises a fluorescent dye selected from the group of Acridine homodimer and derivatives thereof, Acridine Orange and derivatives thereof, 7-aminoactinomycin D and derivatives thereof, Actinomycin D and derivatives thereof, 9-amino-6-chloro-2- methoxy acridine (ACMA) and derivatives thereof, DAPI and derivatives thereof, Dihydroethidium and derivatives thereof, Ethidium bromide and derivatives thereof, EthD- 1 and derivatives thereof, EthD-2 and derivatives thereof, Ethidium monoazide and derivatives thereof, Hexidium iodide and derivatives thereof, bisbenzimide (Hoechst 33258) and derivatives thereof, Hoechst 33342 and derivatives thereof, Hoechst 34580 and derivatives thereof, hydroxystilbamidine and derivatives thereof, LDS 751 and derivatives thereof, Propidium Iodide (PI) and derivatives thereof and Cy-dyes derivatives.
  • a fluorescent dye selected from the
  • Yet another aspect includes a dye selected from a group consisting of blue fluorescent protein (BFP), green fluorescent protein (GFP), photo activatable-GFP(PA-GFP), yellow shifted green fluorescent protein (Yellow GFP), yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (EYFP), cyan fluorescent protein (CFP), enhanced cyan fluorescent protein (ECFP), monomeric red fluorescent protein (mRFPl), kindling fluorescent protein (KFPl), aequorin, autofluorescent proteins (AFPs), JRed, TurboGFP, PhiYFP and PhiYFP-m, tHc-Red (HcRed-Tandem), PS-CFP2 and KFP-Red.
  • the method may also include the step of vacuuming dyed kidney stone dust and/or illuminating the surgical field with polarized light to maximize the visualization of dyed kidney stone dust.
  • Figure 1 FTIR Spectrum of COM Crystals. GATR-FTIR confirms the presence of Calcium Oxalate Monohydrate. Sparse surface area coverage of grown crystals account for differences in signal strength.
  • FIG. 6 Citrate contains three carboxyl groups.
  • Figure 7. Twinned COM crystal dangling from TEM grid Figure 8.
  • Figure 9. HRTEM image of iron oxide nanoparticle adhering to COM crystal Figure 10.
  • FTIR confirmation of peptide functionalization of iron oxide particles Figure 13.
  • (a) The carboxyl functional group on the commercially available iron oxide has a slight affinity for COM crystals,
  • (b) The PAA-coupled particles show a much higher attachment rate.
  • AGM is used to quantify Super-Paramagnetic Iron Oxide (SPIO) attachment to human kidney stone samples,
  • SPIO Super-Paramagnetic Iron Oxide
  • M sat -0.86 emu/gram
  • M sat 0.44 emu/gram
  • Figure 18A and 18B show the effects a magnet on kidney stones in solution coated with the compositions of the present invention.
  • Figure 19A and 19B show that a magnet is able to attract and lift kidney stones in solution coated with the compositions of the present invention.
  • Kidney stone disease is a major health problem affecting 5-10% of the U.S. population and accounts for over $2 billion in annual expenses.
  • compositions and methods are taught herein to assist in the retrieval of biomaterials, e.g., kidney stone fragments, which have been modified to make them ferromagnetic or paramagnetic.
  • the compositions, methods, devices and kits taught herein can selectively attach magnetic or ferrous particles to kidney stone fragments using techniques developed for self-assembled monolayer (SAM) formation and the same may be removed by an intraluminal device that attracts the modified biomaterial.
  • SAM self-assembled monolayer
  • the kidneys are the organs of urinary filtration and excretion where the urine accumulates into and drains from the renal-collecting system.
  • the urinary filtrate enters the collecting system via the renal papillae where the small collecting tubules coalesce.
  • the urine then travels through a branching system of calyces which coalesce to form a single renal pelvis that then drains into the ureter.
  • identifying and fragmenting a stone requires that the collecting system be explored in its entirety with flexible endoscopes passed either up the ureter from the bladder or through a small incision in the flank directly into the kidney.
  • Micro and nanoparticle technology was used to develop the compositions, methods, devices and kits to facilitate endoscopic stone fragment retrieval.
  • the chemistry and physics of stone formation has been well studied.
  • One of the key questions to be answered in this study is the surface chemistry of the stones in situ.
  • novel magnetic nano and microparticles were made that selectively adhere to, e.g., the calcium oxalate crystalline structure of a stone and its fragments.
  • a magnetized wire or working instrument e.g. stone basket
  • dispersed stone fragments will be attracted and gathered in a favorable location in the renal pelvis for extraction. It is anticipated that this revolutionary technology will significantly improve patient safety and reduce operative time and cost by "bringing the stone to the surgeon, rather than the surgeon to the stone.”
  • the present invention may use any of a number of magnetic materials to modify the biomaterial surfaces.
  • a wide variety of permanent magnetic materials may be used with the present invention such as rare earth magnets, ceramic magnets, alnico magnets, which may be rigid, semi-rigid and flexible magnets.
  • flexible magnets are made by impregnating a flexible material such as neoprene rubber, vinyl, nitrile, nylon or a plastic with a material such as iron flakes having magnetic characteristics and will find use with the present invention.
  • the medical device may be rendered magnetic and the material embedded or placed into a base for attachment of the biomaterial may be magnetic.
  • any of a number of magnetic particles may be used, for example, magnetic particles, including Cobalt, Nickel, FePt, SmCo, CoFe, Fe, CoNi, FeCoPt, as well as ceramic materials.
  • Particles may be made from magnetic particles embedded in a non-magnetic or diamagnetic matrix, e.g. silica or polystyrene. Particles of any shape or form, including spherical, nano-crystalline, polycrystalline, cubic, rod-shaped, wire-shaped, or irregular particles may be used.
  • paramagnetic materials will be used.
  • a paramagnetic material refers to a material that only has a magnetic moment in the presence of an magnetic field.
  • the medical devices of the present invention may be made from a wide variety of materials that are, e.g., metallic or non-metallic or magnetic or non-magnetic or elastomeric or non- elastomeric or malleable or non-malleable or the one or more second restraints are metallic or non-metallic or magnetic or non-magnetic or elastomeric or non-elastomeric or malleable or non-malleable so long as the tip or distal end includes a magnetic portion.
  • the shaft that includes the medical device may be magnetic.
  • medical devices surgical instruments
  • the present invention may be made such that the base is metallic or non-metallic or magnetic or non-magnetic or elastomeric or non-elastomeric or malleable or non-malleable.
  • materials include metals, plastics, polymers, wood, alloys, composites and the like.
  • the metals may be made from one or more metals, such as steel, stainless steel, aluminum, titanium, nickel, magnesium, or any other structural metal.
  • Non-limiting examples of plastics or polymers may include: nylon, polyethylene (PE), polypropylene (PP), polyester (PE), polytetraflouroethylene (PTFE), acrylonitrile butadiene styrene (ABS), polyvinylchloride (PVC), or polycarbonate, for example, GE' s Lexan® polycarbonate, and combinations thereof, among other plastics.
  • the tool restraint taught herein may be molded, sintered, machined and/or combinations thereof to form the required pieces to assemble the tool restraint components.
  • the present invention includes attaching magnetic particles to kidney stone fragments for stone retrieval. While commercial products include functionalized magnetic particles, these materials have not been optimized for physiologic use and medical devices (surgical instruments) have not been made or optimized to collect the magnetized stones. Furthermore, it is possible to semi-permanently or permanently trap the paramagnetic particles onto the target biomaterial by using, e.g., a biological coating (e.g. biotin- streptavidin), polymeric, light or UV-curable polymer to permanently bind the kidney stones. It is also possible to semi-permanently or permanently trap the paramagnetic particles onto the target biomaterial by using, e.g., a biological coating (e.g. biotin- streptavidin), polymeric, light or UV-curable polymer to permanently bind the kidney stones once they make contact with the instrument.
  • a biological coating e.g. biotin- streptavidin
  • polymeric, light or UV-curable polymer to permanently bind the kidney stones once they make contact with the instrument
  • Magnetic particle size Commercially available iron oxide particles for magnetic cell separations may be used that are as small as 50 nm and as large as 5 microns, with larger particles having more magnetic attraction and thus faster separations.
  • Example 1 Development of magnetic particles.
  • Magnetic nanoparticles were developed that bond preferentially to the calcium oxalate crystalline structure of most kidney stones.
  • the use of magnetic nanoparticles in medicine was recently reviewed. Typical applications include imaging and tumor treatment.
  • the stone fragment can be attracted to a magnetic tool (wire or stone basket) and moved as needed.
  • Particles of Fe 2 ⁇ 3 or Fe3 ⁇ 4 can be used with no known toxic effects on human tissues. Nevertheless, because of some uncertainty of the toxic effects of these particles, an attempt to prevent passage into general circulation is advisable. Therefore, the nanoparticles will be designed to exceed the diameter of capillary vessels (7 to 8 ⁇ m, which is the diameter of a red blood cell) and possibly collecting ducts (40 to 200 ⁇ m).
  • the first part of the project is to determine the surface chemistry of typical kidney stones.
  • X-ray photoelectron spectroscopy (XPS), grazing angle total reflection FTIR (GATR-FTIR), and biochemical assays are used to determine the surface chemistry.
  • XPS X-ray photoelectron spectroscopy
  • GATR-FTIR grazing angle total reflection FTIR
  • biochemical assays are used to determine the surface chemistry.
  • whether the surface of the fragment is an oxide, a hydroxide, or is covered with an organic residue is determined.
  • One challenge of preparing surfaces is that they are representative of kidney stones that are in vivo in order to determine the surface chemistry.
  • the next step is to determine which chemistry will selectively build a SAM on the stone surface in a solution that is indicative of the solution in a kidney.
  • the surface coverage of the SAM is measured using XPS, GATR-FTIR and fluorescence measurements.
  • the kinetics for film formation is determined by measuring the surface coverage as a function of concentration and time in solution, because there will be limited time for film formation during the kidney stone removal procedure.
  • the next step is to determine the optimal functionalization of the surface of the magnetic particles.
  • Magnetic particles may be purchased or made that can be used to determine the optimal particle size, material and shape.
  • Phosphonic and carboxylic acid functional groups can attach molecules to the magnetic nanoparticles and the target biomaterial, since they will have an oxide surface. Binding of the target under physiologic conditions is required for optimal patient treatment in body lumens.
  • bi-functional molecules are used to selectively attach the magnetic particles or the ferrous particle to the kidney stone fragment.
  • kidney stone target examples include, e.g., an antibody, a peptide, small oligomers (amino acids, lipids, carbohydrates, aptamers, small molecules or nucleic acids) that specifically bind the target.
  • the functionalized magnetic particles are introduced into the lumen and the kidney stone fragments are removed by a magnetically attracting medical device or tool that is inserted into the lumen and that attracts magnetically the modified biomaterial that has been rendered magnetic.
  • the binding pair will generally include a material that is ferrous and a material that is magnetic. Either the biomaterial or the medical device can be ferrous or magnetic and vice versa.
  • the medical device may also include structures that, in addition to the magnetic attraction, may be used for visualizing the target, capture the kidney stone fragments, provide light to the area, permit fluid flow to deliver the functionalized magnetir or ferrous particles or may be used for irrigation.
  • the number of magnetic particles attached to the stone fragments as a function of surface area using SEM and EDAX (energy dispersive X-ray analysis) was determined. Once the magnetic particles are attached to the kidney stone fragments, we will determine the efficiency of attracting the stone fragments to a magnetic wire as a function of fragment size, magnetic particle size, magnetic particle number density, distance between fragment and magnetic wire, viscosity of medium, etc.
  • Certain magnetizing particles may obtained from commercial sources, e.g., Sigma, Bioclone, ESPI, Chemicell, Bangs Labs and Invitrogen.
  • the resulting functionalized materials are characterized using Scanning and Transmission Electron Microscopy (SEM, TEM), Optical Microscopy, Fourier Transform Infrared Spectroscopy (FTIR) and Alternating Gradient Magnetometry (AGM). Optimization studies were undertaken to increase the selectivity and specificity of the nano and micro particles for such biominerals.
  • peptides and protein fragments are known to bind strongly to COM surfaces.
  • a phophorylated 14-mer derived from the protein osteopontin has shown outstanding ability to attach to COM, inhibiting crystal growth, (attached reference 2008 Phosphorylated OPN bind COM.pdf)
  • AARPs 'Aspartic Acid-Rich Peptides', or AARPs
  • Any peptide fragments that bind strongly to COM are a suitable coating for micro- or nanoparticles.
  • Phage Display Combinatorial phage display techniques have been used to identify peptide sequences that bind to calcium-based minerals like calcite (source attached: 2004 Gooch thesis) and to calcium-based biominerals like hydroxyapatite (see patent app referenced in comment).
  • phage display techniques were used to identify peptides that selectively bind to human calcium oxalate kidney stones. Calcium oxalate monohydrate kidney stones extracted from 10 different human patients were combined into a mixture and fragmented into small uniform particles. This stone mixture was used as the target material for a 20-mer phage display library (attached reference: McGuire et al.).
  • Peptide sequences selected from final rounds of phage display show some unique characteristics, including a very high proportion of charged and polar amino acids. More that one third of unique selected peptides contained a methionine at the n-terminus. In particular, two sequences were found to dominate the final round of panning: MGRTVQSGDGTPAQTQPSVN (SEQ ID NO.: 21), designated COM-I, and LRKHADLPGSLSGRVLARPV (SEQ ID NO.: 27), designated COM-2. These peptide sequences, along with peptide sequences that have significant homology with phage-display selected peptides are suitable coating for magnetic particles.
  • Kidney stones are difficult to image conveniently and accurately using currently available techniques, (attached reference: 2004 Stone imaging)
  • the gold standard for imaging kidney stones is the CT scan, which requires significant time and exposure to radiation.
  • the ability to image kidney stones without using harmful radiation, e.g. with MRI technology, or during a surgical procedure, e.g. with ultrasound or x-ray fluoroscopy would represent a significant advantage over current techniques.
  • Peptides that adhere strongly and selectively to COM can be used to deliver imaging contrast agents, such as MRI contrast agents, ultrasound contrast agents, or X-ray contrast agents to these kidney stones, facilitating diagnosis or treatment. Additionally, the ability of these peptides to inhibit or reverse pathological stone formation offers potential therapeutic applications.
  • Calcium-Binding Proteins The classic calcium-binding motif is the EF-hand, which usually contains several carboxylic-rich residues (GIu, Asp) along with Glycine, which provides flexibility. Other proteins that interact with calcium-based biominerals, such as osteopontin and prothrombin fragment, are generally classified as carboxylic acid-rich proteins. Small carboxyl-containing molecules such as citrate are known to have an inhibitory effect on the growth of Calcium Oxalate crystals in healthy urine.
  • Polypeptide Functionalized Microparticles Attached Poly-aspartic acid (PAA) to commercially available iron oxide microparticles using a standard carbodiimide coupling protocol. Confirmed attachment using FTIR. Exposed synthetic COM crystals to iron oxide particles in solution for 30 minutes, rinsed wafers with DI water and then dried with nitrogen prior to examination.
  • PAA Poly-aspartic acid
  • 1 -micron particles coated with poly-aspartic acid can be incubated in phosphate-buffered saline (PBS) with fragmented kidney stones for 5 minutes, and after this brief time, stone fragments can be retrieved from a simulated bladder with a small magnetized surgical instrument.
  • PBS phosphate-buffered saline
  • Figures 18A and 18B show that a magnet approaching 3-4 mm stone fragments (18A); magnet attracts functionalized stone fragments from 1 cm (18B).
  • Figures 19A and 19B shows that a magnet approaching 1-2 mm stone fragments (19A); magnet with attached functionalized stone fragments (19B).
  • iron oxide-coupled kidney stone fragments can be magnetically manipulated using small permanent magnets.
  • magnetic particles can be bound selectively to stone fragments, in either case, the particle (whether ferrous or magnetic) should not to urothelial surfaces (or with the least amount of binding possible).
  • Magnetic particles with larger magnetic moments and improved surface coatings can also be used to facilitate use of smaller magnets, reduce incubation times, and maintain selectivity for kidney stones over urothelium.
  • the examples above show the development of paramagnetic micro- and nanoparticles that can selectively attach to calcium stones.
  • the magnetic field can be generated by one or more permanent or electromagnets.
  • the one or more magnetic fields can be generated by magnets that are individually hand-held or supported using a custom- made arm (manual or robotic).
  • the optimal design of the magnets may include engineering solutions such as "magnetic flux focusing.”
  • the size specifications will depend on the needed magnetic force and will depend on patient size and distance from skin to stones.
  • the size and power of the magnetic field applied to the target tissue using magnetic tools will depend on the size of the target fragments, extent of coating, and friction encountered at the target size.
  • Magnetic tools are applied, directed and focused in such a manner that stones or stone fragments can be manipulated and moved by the surgeon to different locations within the urinary collecting system (calyx, pelvis, ureter or bladder). It may be possible for the surgeon to move the stone from the kidney or ureter through the collecting system and into the bladder/urethra. It is also envisioned that during a ureteroscopy or percutaneous nephrolithotomy (through the back), the surgeon will be able to magnetically move the stone fragments into an position for favorable stone extraction. For example, in some cases the surgeon may not be able to grasp the stone with a basket or grasper due to a poor angle, but with magnetization, the surgeon will be able to move the stone to allow easy grasping and removal.
  • Porcine urothelium For Porcine urothelium it was found under the tissue microscope that the magnetic particles were seen with decreasing density after serial washings and no iron oxide particles were seen on H&E or Prussian blue stains after the washes were completed.
  • compositions and methods of the present invention were used to successfully demonstrated that micro- and nano-particles can be attached to calcium-based biominerals. Further studies can focus on improving the protein coating on the particles to enhance selectivity for specific biominerals, utilizing the quantitative methods outlined here.
  • Example 5 Attachment of fluorescent magnetic particles to kidney stones for detection and retrieval and tools to find and retrieve particles. This Example demonstrates that fluorescent materials can be attached to small kidney stone fragments following fragmentation to help surgeons visualize and remove all pieces using specialized instruments, thus reducing the chance of recurrence.
  • the invention presented in this disclosure is the idea that either the magnetic particles or the proteins used to attach the magnetic particles to the kidney stones could be made fluorescent. When the particles are illuminated with a specific wavelength of light, they will fluoresce at a different, unique wavelength that is not present in the background illumination, making the stone fragments visible to the surgeon. Fluorescent materials may be selected with absorption wavelengths that are not strongly absorbed by the saline solution and blood that is present in the kidney during the surgical procedure, such as in the ultraviolet region.
  • the emitted light is a unique color that is easily distinguished from the background-reflected light in the kidney and is at a wavelength that is not strongly absorbed by the solution environment in the kidney during the procedure.
  • a light source is selected of the proper wavelength and intense enough to fluoresce the functionalized stone fragments so the surgeon can see them through the endoscope, e.g., a light emitting diode of the proper wavelength may be positioned to transmit the light through the endoscope or the LEDs can be positioned at the tip or delivered through the endoscope.
  • An organic light emitting diode (OLED) would have the advantage that an annular light source that is very thin could be added to the end of the endoscope, which could be turned on only when looking for fragments.
  • the OLED light source could be multiple colors so that it could be used for general illumination during the procedure, as well as for exciting the particles.
  • the amount of x-ray radiation the patient receives is decreased because the need to use fluoroscopy to look for small stone fragments during the surgical procedure will be reduced or eliminated.
  • the ability to tune both the photoluminescent absorption and emission energy allow the user to use excitation energies that are not strongly absorbed by the bulk of the materials present during the procedure, greatly increasing the sensitivity of the technique.
  • using an annular OLED tunable light source should reduce the amount of power required to illuminate the working environment during the procedure, decreasing the chance of bringing a hot surface in contact with the tissue.
  • the fluorescent tag may be included as part of the protein that is used to attach the magnetic particles to the stone fragments.
  • photoluminescent material either organic or inorganic
  • inorganic photoluminescent phosphors could be used by simply incorporating the phosphor material in the polystyrene spheres with the magnetic material.
  • polystyrene spheres with iron oxide particles can be made depending on the fluorescent material used.
  • materials for use with the present invention include photoluminescent phosphors. The specific phosphor can be determined by the required absorption and emission energies.
  • Suitable labels or dyes or fluorophores include, without limitation, any atomic element amenable to attachment to a specific site in a polymerizing agent or dNTP, especially fluorescent dyes such as d-Rhodamine acceptor dyes including dichloro[Rl 10], dichloro[R6G], dichloro [TAMRA], dichloro[ROX] or the like, fluorescein donor dye including fluorescein, 6-FAM, or the like; Acridine including Acridine orange, Acridine yellow, Proflavin, or the like; Aromatic Hydrocarbon including 2-Methylbenzoxazole, Ethyl p-dimethylaminobenzoate, Phenol, Pyrrole, benzene, toluene, or the like; Arylmethine Dyes including Auramine O, Crystal violet, Crystal violet, Malachite Green or the like; Coumarin dyes including 7-Methoxycoumarin-4-acetic acid, Coumarin 1, Coumarin 30, Coumarin 314, Cou
  • fluorescent dye examples include Acridine homodimer and derivatives thereof, Acridine Orange and derivatives thereof, 7-aminoactinomycin D and derivatives thereof, Actinomycin D and derivatives thereof, 9-amino-6-chloro-2-methoxyacridine (ACMA) and derivatives thereof, DAPI and derivatives thereof, Dihydroethidium and derivatives thereof, Ethidium bromide and derivatives thereof, EthD-1 and derivatives thereof, EthD-2 and derivatives thereof, Ethidium monoazide and derivatives thereof, Hexidium iodide and derivatives thereof, bisbenzimide(Hoechst 33258) and derivatives thereof, Hoechst 33342 and derivatives thereof, Hoechst 34580 and derivatives thereof, hydroxystilbamidine and derivatives thereof, LDS 751 and derivatives thereof, Propidium Iodide (PI) and derivatives thereof and Cy-dyes derivatives.
  • ACMA 9-amino-6-chloro-2-methoxy
  • proteins that are fluorescent include blue fluorescent protein (BFP), green fluorescent protein (GFP), photo activatable-GFP(PA-GFP), yellow shifted green fluorescent protein (Yellow GFP), yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (EYFP), cyan fluorescent protein (CFP), enhanced cyan fluorescent protein (ECFP), monomeric red fluorescent protein (mRFPl), kindling fluorescent protein (KFPl), aequorin, autofluorescent proteins (AFPs), JRed, TurboGFP, PhiYFP and PhiYFP-m, tHc-Red (HcRed-Tandem), PS-CFP2 and KFP-Red.
  • BFP blue fluorescent protein
  • GFP green fluorescent protein
  • PA-GFP photo activatable-GFP
  • ZFP yellow shifted green fluorescent protein
  • YFP yellow fluorescent protein
  • EYFP enhanced yellow fluorescent protein
  • CFP cyan fluorescent protein
  • ECFP enhanced cyan fluorescent protein
  • KFPl monomeric red fluorescent protein
  • KFPl kindling fluorescent protein
  • the present invention allows the surgeon to visualize stone 'dust' in the surgical field. For example, after the surgeon finishes the removal of larger stone fragments, they turn off the visible white light of the scope and turn on a narrow spectrum light source (like an OLED) to 'vacuum up' the remaining stone dust under fluorescent or polarized light visualization using a magnetic wand or other magnetic instrument.
  • a dye, visible or fluorescent allows the surgeons to ensure that no magnetic particles are being left inside the kidneys and maximize the removal of possible stone fragments or dust that could serve as re-nucleation sites.
  • compositions of the invention can be used to achieve methods of the invention.
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • the term “or combinations thereof as used herein refers to all permutations and combinations of the listed items preceding the term.
  • A, B, C, or combinations thereof is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.
  • expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth.
  • BB BB
  • AAA AAA
  • MB BBC
  • AAABCCCCCC CBBAAA
  • CABABB CABABB
  • compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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Abstract

La présente invention concerne des compositions, des procédés, des dispositifs et des kits de magnétisation d'une particule biologique en mettant une particule biologique en contact avec une particule ferreuse ou magnétique capable de se lier spécifiquement à la particule biologique, et en faisant réagir la particule biologique avec la particule ferreuse ou magnétique dans des conditions physiologiques, la particule ferreuse ou magnétique amenant la particule biologique à pouvoir être attirée magnétiquement.
PCT/US2008/085038 2007-11-27 2008-11-26 Fonctionnalisation de micro et nanoparticules en vue de les fixer de manière sélective sur des surfaces biominérales de calcium Ceased WO2009070766A2 (fr)

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US99060207P 2007-11-27 2007-11-27
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